Seeking to identify melanoma-associated genes by comparing gene expression in uncultured primary melanoma specimens with those in nevi, from which melanomas often are known to arise, we applied subtractive suppression hybridization. Generating a subtracted library of candidate genes up-regulated in primary melanomas, this library contained cDNA fragments of the genes encoding heat shock cognate protein (HSP73) and major histocompatibility complex (HLA-DR) which were overexpressed in further 19 independent melanoma resection specimens on cDNA Southern blots when compared to 19 acquired melanocytic nevi. Upon immunohistochemistry, HSP73 protein expression was detected in the cytoplasm of melanoma cells in primary tumours and metastases. In primary melanomas, the proportion of HSP73 protein expressing cells correlated with tumour thickness according to Breslow which was statistically significant. HSP73 immunostaining was stronger in melanoma metastases when compared with acquired melanocytic nevi which was statistically significant. In addition to melanoma, gastric and uterus cancer tissues exhibited higher HSP73 mRNA expression on a matched tumour/normal cDNA array than their normal counterparts which was statistically significant. Participating in the regulation of folding, assembly and degradation of proteins and protecting cellular proteins from the damage caused by cellular stress like hypoxia or changes in cellular pH, elevated HSP73 expression possibly confers proliferative advantage on melanoma cells.